The invention relates to new compounds and drugs containing the new compounds as active, pharmaceutical ingredients.
Likewise, the invention relates to the use of the new compounds for the preparation of drugs for the treatment of Alzheimer""s disease and related dementia conditions, as well as for the treatment of Langdon-Down Syndrome (mongolism, trisomy 21).
The acid addition salt of galanthamine, which has the chemical structure 
as well as some of its analog, are known as active pharmaceutical ingredients having an inhibitory effect on the synaptic enzyme, acetylcholine esterase. Galanthanine is therefore used pharmacologically for paralysis symptoms resulting from polio mellitus and for different diseases of the nervous system.
Galanthamine and some of its derivatives are also used for the symptomatic treatment of Alzheimer""s disease and related dementia conditions (EP 236 684 B1).
Chemically, galanthamine is an alkaloid of the morphine group, which can be obtained from snowdrops (Galanthus woronowii, G. nivalis etc.) and other Amaryllidaceae.
Aside from obtaining galanthamine from plant sources, chemical methods of synthesizing galanthamine and its analogs, including its acid addition salts, have also become known (WO 95/27715).
The Down syndrome is attributed to a tripling of chromosome 21, that is, the patients have a set of 47 chromosomes instead of 46. This can be demonstrated relatively simply cytologically. Trisomy 21 is associated with moderate to severe mental impairment and a series of symptoms of physical dysmorphism. A causative treatment is not possible at the present time. The existing impairment can be influenced by selective therapeutic measures. However, a distress usually remains.
The new inventive compounds are new benzazepine derivatives, particularly derivatives of benzofuro[3a, 3, 2, ef] [2] benzazepine.
They are compounds of the general formula (I) 
in which
R1, R2 either are the same or different and represent
hydrogen, F, Cl, Br, I, CN, NC, OH, SH, N02, SO3H, NH2, CF3 or
a lower (C1-C6), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkoxy group or
an amino group, which is substituted by one or two or different lower (C1-C6), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkyl carbonyl or (Ar) alkoxy carbonyl or
a COOH, COO(Ar) alkyl, CONH, CON(Ar) alkyl group or
represents xe2x80x94(CH2)nxe2x80x94Cl, xe2x80x94(CH2)nxe2x80x94Br, xe2x80x94(CH2)nxe2x80x94OH,xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94CN, xe2x80x94(CH2)nxe2x80x94NC, in which
it is also possible to define R1-R2 jointly as xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, (CH2)nxe2x80x94Oxe2x80x94, with n=1 to 3.
R3xe2x95x90R1, particularly OH and OCH3 and furthermore
R2-R3 can jointly form: xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94, with n=1 to 3
R4, R5: either are both hydrogen or, alternatively, any combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, (Ar) alkinyl with
Sxe2x80x94R8, wherein R8 is hydrogen or a lower (C1-C10), optionally branched, optionally substituted (Ar) alkyl group
SOxe2x80x94R8, SO2R8 
OH, O-protective group (such as TMS, TBDMS)
Oxe2x80x94CSxe2x80x94Nxe2x80x94R8 (thiourethanes)
Oxe2x80x94COxe2x80x94Nxe2x80x94R9, wherein R9 has the following meaning: 
Oxe2x80x94COxe2x80x94R5 (ester, R8 see above), in particular, also esters with the substitution pattern of amino acids such as 
Furthermore: R4, R5=jointly hydrazone (xe2x95x90Nxe2x80x94NHxe2x80x94R10, xe2x95x90Nxe2x80x94N(R10, R11), Oximes (xe2x95x90Nxe2x80x94Oxe2x80x94R11), wherein R10 is hydrogen, a lower (C1-C6), optionally branched, optionally substituted (Ar)-alkyl or (Ar)-alkyl carbonyl or (Ar)-alkyl carbonyloxy group as well as a sulfonic acid group, such as a tosyl and mesyl group and R11 is hydrogen, a lower (C1-C6), optionally branched, optionally substituted (Ar)-alkyl or (Ar)-alkyl carbonyl group, as well as a sulfonic acid group, such as a tosyl and mesyl group.
as well as substituents of the type 
Y1, Y2xe2x95x90O, S, NH or Nxe2x80x94R10 (excess valences in each case are xe2x80x94H)
wherein, in the event that R4xe2x95x90H, R5 can also be OH and, in the event that R5xe2x95x90H, R4 can also be OH.
G1, G2:jointly or separately have the meaning:
xe2x80x94C(R13, R14)xe2x80x94, wherein R13, R14 can be hydrogen, OH, a lower, optionally branched, optionally substituted (Ar)-alkyl, aryl, (Ar)-alkoxy or aryloxy group or jointly an alkyl spiro group (C3 to C7 spiro ring).
Furthermore, G1 and G2 jointly represent 
xe2x80x83with m=1 to 7
G3: represents CH2 or xe2x95x90CO
R6 represents a group xe2x80x94(G4)pxe2x80x94(G5)qxe2x80x94G6 with p, q=0 to 1, in which G4 satisfies the following definition
xe2x80x94(CH2)rxe2x80x94, xe2x80x94C(R15,R16)xe2x80x94(CH2)rxe2x80x94, with R=1 to 6 and R15, R16=hydrogen, lower, optionally branched or optionally substituted (Ar)-alkyl, cycloalkyl, aryl groups
xe2x80x94Oxe2x80x94 or xe2x80x94NR15
with s=1 to 4, t=0 to 4
xe2x80x83that is an ortho, meta or para disubstituted aromatic 
xe2x80x83wherein G7xe2x95x90NR15, O or S,
G5 can be identical with or different from G4 and, in the event that P=1, additionally represents xe2x80x94Sxe2x80x94,
G6 fulfills the following definition: 
with
R17, R18, R19 and R20 individually or jointly are the same or different, hydrogen, lower, optionally branched, optionally substituted (Ar)-alkyl, cycloalkyl or aryl groups, wherein R17 and R18 and R19 and R20 can jointly form a cycloalkyl group (with a ring size of 3-8)
G8xe2x95x90O, S, NH, NR21xe2x80x94(CH2)nxe2x80x94,
R21xe2x95x90CHO, COOR17 or a heteroaryl group, which is unsubstituted or substituted identically or differently by one or several F, Cl, Br, I, NO2, NH2, OH, alkyl, alkyloxy, CN, NC or CF3, CHO, COOH, COOalkyl, SO3H, SH or S-alkyl groups, (heteroaryl being, in particular, 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or
a methyl group, which is substituted by 1-3 phenyl groups, which are unsubstituted or substituted identically or differently by one or more F, Cl, Br, I, NO2, NH2, alkyl, alkyloxy, CN, NC or CF3 groups,
Furthermore, G6 can be: 
xe2x80x94CHO, COOR17, xe2x80x94CONR17 
a lower, optionally branched, optionally substituted (Ar)-alkyl, (Ar)-alkenyl, (Ar)-alkinyl, cycloalkyl or aryl groups,
xe2x80x94Oxe2x80x94R17, xe2x80x94NR17R18, phthalamido, xe2x80x94CN or xe2x80x94NC.
R7 is identical with R6 or represents xe2x80x94Oxe2x80x94(xe2x88x92) (N-oxide) or a free electron pair (e-pair), wherein R6 and R7 can also form a common ring, 3 to 8 carbon atoms in size and
[X] exists only if, and represents an ion of a pharmacologically usable inorganic or organic acid, when R5 and R6 are present and the nitrogen atoms thus carries a positive charge.
Zxe2x95x90N or N+ in the event that R6 and R7 are present jointly and R7 is not Oxe2x88x92.
A special case of the new compounds of the general formula (I) are the compounds of the general formula (II) 
wherein the groups have the meanings described for formula (I). This formula arises formally out of formula (I), in that the bond from C1 to the furan oxygen is broken and, instead, a bond between C1 and Z is formed directly.
Furthermore, the invention comprises the new, substituted, bridged bases of the general formula (III) and their synthesis, and particularly to 2,5-diazabicyclo [2.2.1]heptane: 
wherein R22 
is a (hetero) aryl group, which is unsubstituted or substituted identically or differently by one or several F, Cl, Br, I, NO2, NH2, OH, alkyl, alkoxy, CN, NC or CF3, CHO, COOH, COOalkyl, SO3H, SH or S-alkyl groups or
a methyl group, which is substituted by two phenyl groups, which are substituted identically or differently by one or more F, Cl, Br, I, NO2, NH2, OH, alkyl, alkoxy, CN, NC or CF3, CHO, COOH, COOalkyl, SO3H, SH or S-alkyl groups,
R17, R18, n, s having the meanings given for the general formula (I) and
R23=xe2x80x94(G5)qxe2x80x94(G4)pxe2x80x94G9 
wherein G4 and G5 have the meanings given for the general formula (I) and G9 is defined as:
Hydrogen, F, Cl, Br, I, OH, O-ts, O-ms, O-triflate, COOH, COCl CHO, xe2x80x94Oxe2x80x94R17, xe2x80x94NR17R18, phthalimido, xe2x80x94CN or xe2x80x94NC or by other groups suitable for nucleophilic substitutions, addition reactions, condensation reactions, etc.
Examples of these types of compounds are: 
These compounds of the general formula (III) represent not only a pharmaceutically interesting class of compounds, but also find use as substitutents in a plurality of basic compounds. The compound 105 to 109 represent the compounds.
The inventive drugs can be used successfully for the treatment of Alzheimer""s disease and related dementia conditions, as well as for the treatment of Langdon-Downs syndrome.
The invention likewise relates to the use of the compounds used above for the preparation of drugs for the treatment of Alzheimer""s disease and related dementias, as well as for the treatment of Langdon-Downs syndrome.
Particularly preferred pursuant to the invention are the compounds named in the survey below. In the survey, the ACHE inhibition values (IC50, that is, the 50% inhibition concentration) of the inventive compounds, which are one of the factors, which determine the effectiveness, are also given.
The inhibition of acetylcholine esterase was determined by a modified method of Ellmann (reference 44), human serum from a pool of 10 test subjects being used as serum.
Method: 520 xcexcL of solution of the test substance (concentrations of 10xe2x88x924 to 10xe2x88x927 and, in exceptional cases, up to 10xe2x88x929 moles/liter were used) in 0.02 M tris(hydroxymethyl)aminomethane solution, buffered with HCl to a pH of 7.8 and 400 xcexcL of m-nitrophenol solution (Sigma Diagnostics, Art. 420xe2x80x944) were incubated in the semi-micro cuvette at 37xc2x0 C. with 40 xcexcL of cholinesterase solution (Sigma Diagnostics, Art. 420-MC, diluted 1:15 with water) and 160 xcexcL of serum and the change in the absorption was measured over 5 minutes against a comparison sample in a Beckmann DU-50 spectrophotometer with a kinetics program. The values were given as a percentage of the comparison sample and the inhibiting concentration (IC50) was calculated from the course of the curve.
Survey of the New Compounds of the Type of the General Formula:
The general formula (II) is a special case of the general formula (I)
The compounds, contained in drugs pursuant to the invention, can be administered in any suitable chemical or physical form, such as an acid addition salt. For example, they can be administered as hydrobromide, hydrochloride, methyl sulfate or methyl iodide.
The inventive drugs can be administered to patients orally or by subcutaneous or intravenous injection or intracerebroventricularly by means of an implanted container.
It may be necessary to start with doses lower than effective ones.
Typical dosing rates when administering drugs containing the active ingredients proposed pursuant to the invention depend on the nature of the compound used and on the condition of the patient. Typically, dosage rates lie in the range of 0.01 to 1.0 mg per day per kg of body weight, depending on the age, the mental condition and other medication of the patient.
The inventive drugs may be present in the following specific formations:
tablets or capsules containing 0.5 to 50 mg
parenteral solution containing 0.1 to 30 mg/mL liquid formulation for oral administration in a concentration of 0.1 to 15 mg/mL
The inventive compounds can also be a transdermal system, in which 0.1 to 10 mg are released per day.
A transdermal dosing system consists of a reservoir layer, which contains 0.1-30 mg of the active substance as free base or salts, if necessary, together with a penetration accelerator, such as dimethyl sulfoxide, or a carboxylic acid, such as octanoic acid, and a skin-neutral polyacrylate, such as hexyl acrylate/vinyl acetate/acrylic acid copolymer together with a plasticizer, such as isopropyl myristate. The covering is an outer layer, which is impermeable to the active ingredient, such as metal-coated, siliconized polyethylene Band-Aid with a thickness of, for example, 0.35 mm. A dimethylaminomethyl acrylate/methyl acrylate copolymer in an organic solvent, for example, is used to produce an adhesive layer.
Some examples of methods, by means of which inventive compounds can be synthesized, are given below.